The present invention relates to an iontophoresis device suitable for percutaneous and mucosal applications of drugs and in particular to iontophoresis device of the type, which is activated before practically using as well as a method of assembling the same.
Recently, there have been developed a variety of dosage forms in the field of pharmaceutical preparations for external use (external pharmaceutical preparations) and the development has gradually become a matter of great concern. The reason for this is as follows: The administration of a drug, which may have a local or systemic pharmacological action, through the skin or the mucous membranes has many advantages. For instance, the sustained-release effect of the drug can be expected; such administration is not greatly influenced by the metabolism due to the first-pass effect in the liver unlike the oral administration and permits the effective use of the drug; and drugs accompanied by, for instance, liver disorders can relatively safely be administered.
However, the normal skin naturally has a protective effect against external stimulations and this makes the absorption and penetration of a drug through the skin relatively difficult. For this reason, in the existing circumstances, a drug is not absorbed in an amount sufficient for ensuring a sufficient effect even if the drug is administered in a dosage form for external use. Moreover, in the administration method, which makes use of absorption routes through biological membrane other than the skin, such as mouth, rectum, oral cavity and nose as well as the sublingual route, it is difficult to penetrate into or transmit through the related biological membrane depending on the kind of drugs and therefore, there have been known a large number of drugs having low bioavailability. Accordingly, there has been desired for the development of an absorption-promoting method, which can sufficiently enhance the permeability, penetrability and absorbency of a drug against the skin and other biological membranes, can ensure a sufficient pharmacological efficacy of the drug and is substantially free of, for instance, its local and systemic toxicity and is highly useful and safe.
As such absorption-promoting methods, there have recently been known, chemically promoting methods, which make use of absorption-promoting agents, and physically promoting methods in which iontophoresis or phonophoresis is employed. Among them, the iontophoresis has unexpectedly attracted special interest recently and has been expected as an administration method, which can solve the foregoing problems.
The iontophoresis is a method for the administration of a drug by applying a voltage to the skin or a mucous membrane to electrically induce the migration of an ionic drug and to thus administrate the drug through the skin or a mucous membrane. In general, an iontophoresis device is provided with a pair of electrodes for iontophoresis, i.e., an anode and a cathode and the device is so designed that these electrodes are arranged on or attached to the skin at a predetermined distance apart from one another and an electric current generated by a current generator is guided to these electrodes to thus carry out treatments.
Moreover, this iontophoresis device has a structure comprising a combination of these electrodes and a layer, which stores a drug therein, and a variety of additives for maintaining the drug efficacy are optionally enclosed in the layer in addition to a predetermined amount of the effective component in order to keep a desired blood concentration in the body over a long period of time.
The iontophoresis device of this type is, for instance, disclosed in Japanese Un-Examined Patent Publication Nos. Sho 62-268569, Hei2-131779, Hei3-268769 and Hei3-45271 and TOKUHYO Nos. Hei 3-504343 and Hei 3-504813.
However, if a drug (such as physiologically active peptides), which suffers from a problem of the solubility in water, ,is used in these iontophoresis device, the predetermined amount of the drug may be reduced due to the partial decomposition thereof with time. Moreover, if the drug is administered in a high concentration, the drug may be diluted during storing.
If a peptide drug is percutaneously administered by the iontophoresis, it is common that the drug is not maintained in an iso-electric environment, but is kept in an acidic or basic environment. For this reason, the stability of additives, which are incorporated into the device to assist the development of the pharmacological efficacy of the biologically active substance, is greatly influenced by such acidic or basic environment and accordingly, the drug efficacy may be reduced.
Moreover, it has been recognized that when physiologically active peptides are stored in the form of solutions, members constituting the pharmaceutical preparation may be adsorbed on the peripheral site and it is thus quite difficult to maintain a desired concentration of the drug over a long period of time.
As other problems, it has been reported that in a device, which is designed in such a manner that an electrically conductive layer containing a drug in the form of a solution is directly in contact with the electrodes immediately after the electrical charging, the drug is electrolytically decomposed on the electrode surface during electrically charging the device. Accordingly, it would be doubtful whether the decomposed drug through its internal absorption adversely affects the human body.
There have been proposed a variety of methods for the solution of such a problem. For instance, Japanese Un-Examined Patents Publication No. Sho 63-102768 and U.S. Pat. No. 5,310,404 disclose a method, which comprises the steps of arranging a capsule or porch enclosing water or an electrolyte solution above the electrode structure and breaking the capsule or porch immediately before the practical use to thus impregnate the drug-support layer therewith. This method is excellent in that the drug can be stored in a stable condition (dry state), but it is still insufficient since it takes a long time for uniformly permeating the moisture into the whole drug-support layer and the drug efficacy may be reduced due to the dilution of the drug.
In addition, Japanese Patent No. 2,542,792 discloses a method in which a drug-support layer and an electrode layer containing an electrolyte are separately disposed in distinct compartments, which are hinged to one another and then piling one upon another at the hinged portion to thus activate the device. This method permits the improvement in the long-term stability of a drug, but any means for activating the device upon application is not sufficiently devised and therefore, the method may include a lot of causes for artificial errors and cannot achieve sufficiently uniform distribution of the drug after the activation of the device.
Moreover, Japanese Un-Examined Patent Publication No. Hei 3-94771 discloses a device, which is so designed that a selective ion-permeable membrane (such as an ion-exchange membrane) is arranged such that the membrane is adjacent to the skin side of a water-support portion thereof, while a drug is dried and adhered to the side of the selective ion-permeable membrane, which is in contact with the living body, to thus prevent any dilution of the drug and to realize the administration of a trace a mount of the drug to a local site in a high concentration.
Japanese Un-Examined Patent Publication No. Hei 9-201420 discloses a device for iontophoresis, in which an electrode structure layer, a solvent-support layer and a drug-support layer containing a dried physiologically active substance are put in a layer structure in this order and a water-impermeable separator layer is positioned between the solvent-support layer and the drug-support layer. This device is so designed that the solvent-support layer is automatically brought into contact with the drug-support layer by pulling out the separator layer upon activation. This device is quite excellent in that the occurrence of any artificial error is prevented when assembling the device. In this device, however, the solvent-support layer and the drug-support layer are accommodated in the same package, the stability of the drug may be reduced due to any leakage of the solvent from the solvent-support layer and accordingly, it is difficult to ensure the quality of the device. Moreover, even if it were technically possible to completely prevent the leakage of the solvent, the cost required for the development of such a technique would be very high.
As has been described above, there has not yet been developed any iontophoresis device, which can ensure the long-term stability of a drug, can easily and accurately be assembled immediately before the practical use thereof and permits the elimination of any artificial error as much as possible.
Accordingly, it is an object of the present invention to provide an iontophoresis device, which can ensure the long-term stability of a drug and can easily be assembled immediately before the application as well as a method of assembling the device.
The foregoing object of the present invention can be accomplished by providing an iontophoresis device, in which an electrode portion equipped with a drug-dissolving portion and a drug portion equipped with a drug-support are provided with alignment structures respectively so that the drug-support and the drug-dissolving portion are brought into contact with one another by coinciding the alignment structure of the drug portions with that of the electrode portion. These alignment structures are, for instance, openings formed on the electrode portion and the drug portion, respectively. These portions can accurately and rapidly be aligned by aligning these openings of the electrode and drug portions with one another.
In addition, the device is also designed in such a manner that an electric current-supply portion is provided with the same alignment structure, the alignment structure is coincided with that of the electrode portion to thus contact the current-supply portion with the electrode portion. The alignment structure for the current-supply portion may be an electrode terminal. In this case, the alignment structure may be formed on the terminal connected to the current-supply portion through a connecting cord.
Alternatively, a connector having the same alignment structure is disposed and the alignment structures of every portions are coincided with one another to thus connect them to the current-supply portion and the connector through the electrode portion. If some of these alignment structures are formed from an electrically conductive material, such alignment structures may be used as electrical connection means.
The drug portion of this iontophoresis device is stored as a package separated from the parts such as those for the current-supply and electrode portions, prior to the practical use. Thus, the device is designed such that the electrode and drug portions are mechanically connected or the electrode and current-supply portions are electrically connected to one another. A means for holding this arrangement used herein is, for instance, electrode terminals of the current-supply portion or conductive snap connector or an auxiliary stand for assemblage. As has been described above, the device according to the present invention may be a set of units in which the electrode portion equipped with an alignment structure and the drug portion equipped with the same alignment structure are separately packaged. In addition, the current-supply portion or the connector having an identical alignment structure and an auxiliary stand for alignment are also packaged separately from the drug portion, in this set of units.
The electrode portion (electrode unit) used herein comprises a member holding a conductive layer, a wiring connected to the conductive layer and an alignment structure formed on at least one of the wiring and the member. The alignment structure is an opening formed on at least one of the wiring and the member. On the other hand, the drug portion (drug unit) comprises a drug-support, a peelable cover for protecting the drug-support and an alignment structure formed on the cover. In this case, the alignment structure is an opening formed on the edge of the cover.
The method of assembling the iontophoresis device according to the present invention comprises the steps of peeling off a cover material disposed on an electrode portion; coinciding an alignment structure of the electrode portion with that of a drug portion to thus dispose a drug-support of the drug portion on a drug-dissolving portion; peeling off a cover of the drug-support on the side of the drug-dissolving portion; and fixing the drug-support to the electrode portion. In this device, a cover is also positioned on the drug-support opposite to the side of the drug-dissolving portion. In this case, however, if an opening is formed on the cover, the assemblage of this device can be completed without peeling off the cover. On the other hand, if any opening is not formed on the opposite cover, the assemblage of the device is completed after peeling off at least part of the cover. More specifically, the opposite cover may completely be peeled off or the part of the cover other than the portion provided with the alignment structure may, for instance, be peeled off.
The electrode portion and the drug portion can be aligned with one another, while making use of the alignment structure disposed on an auxiliary stand, a current-generating portion or a connector. In this case, the both alignment structures of the electrode and drug portions are constituted by openings, while the alignment structure of the auxiliary stand is constituted by an alignment rod capable of being inserted into the opening. On the other hand, the alignment structures for the current-generating portion and the connector may be electrode terminals thereof.
Thus, an iontophoresis device and a method of assembling the same can be provided, which can ensure the long-term stability of a drug, whose assembling operations are easy and accurate upon application and which can eliminate any cause of artificial errors as much as possible.